Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Progranulin protects against amyloid β deposition and toxicity in Alzheimer's disease mouse models

Abstract

Haploinsufficiency of the progranulin (PGRN) gene (GRN) causes familial frontotemporal lobar degeneration (FTLD) and modulates an innate immune response in humans and in mouse models. GRN polymorphism may be linked to late-onset Alzheimer's disease (AD). However, the role of PGRN in AD pathogenesis is unknown. Here we show that PGRN inhibits amyloid β (Aβ) deposition. Selectively reducing microglial expression of PGRN in AD mouse models impaired phagocytosis, increased plaque load threefold and exacerbated cognitive deficits. Lentivirus-mediated PGRN overexpression lowered plaque load in AD mice with aggressive amyloid plaque pathology. Aβ plaque load correlated negatively with levels of hippocampal PGRN, showing the dose-dependent inhibitory effects of PGRN on plaque deposition. PGRN also protected against Aβ toxicity. Lentivirus-mediated PGRN overexpression prevented spatial memory deficits and hippocampal neuronal loss in AD mice. The protective effects of PGRN against Aβ deposition and toxicity have important therapeutic implications. We propose enhancing PGRN as a potential treatment for PGRN-deficient FTLD and AD.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Differential expression of PGRN in AD brains and in young and aged APP transgenic mice.
Figure 2: PGRN deficiency exacerbates Aβ-mediated behavioral and neuronal deficits and modulates the innate immunity in 9- to 13-month-old APPlow mice.
Figure 3: Microglial PGRN deficiency increases plaque deposition and impairs phagocytosis.
Figure 4: Microglial PGRN protects against Aβ toxicity.
Figure 5: PGRN overexpression in the hippocampus decreases amyloid plaque load in 5xFAD mice.
Figure 6: Lentiviral PGRN overexpression prevents neuronal loss and hippocampus-dependent memory deficits in 5xFAD mice.

References

  1. 1

    Daniel, R., He, Z., Carmichael, K.P., Halper, J. & Bateman, A. Cellular localization of gene expression for progranulin. J. Histochem. Cytochem. 48, 999–1009 (2000).

    CAS  PubMed  Article  Google Scholar 

  2. 2

    Daniel, R., Daniels, E., He, Z. & Bateman, A. Progranulin (acrogranin/PC cell–derived growth factor/granulin-epithelin precursor) is expressed in the placenta, epidermis, microvasculature, and brain during murine development. Dev. Dyn. 227, 593–599 (2003).

    CAS  PubMed  Article  Google Scholar 

  3. 3

    Petkau, T.L. et al. Progranulin expression in the developing and adult murine brain. J. Comp. Neurol. 518, 3931–3947 (2010).

    PubMed  Article  Google Scholar 

  4. 4

    Baker, M. et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442, 916–919 (2006).

    CAS  PubMed  Article  Google Scholar 

  5. 5

    Cruts, M. et al. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442, 920–924 (2006).

    CAS  PubMed  Article  Google Scholar 

  6. 6

    Gass, J. et al. Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum. Mol. Genet. 15, 2988–3001 (2006).

    CAS  PubMed  Article  Google Scholar 

  7. 7

    Yin, F. et al. Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice. J. Exp. Med. 207, 117–128 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8

    Petkau, T.L. et al. Synaptic dysfunction in progranulin-deficient mice. Neurobiol. Dis. 45, 711–722 (2012).

    CAS  PubMed  Article  Google Scholar 

  9. 9

    Yin, F. et al. Behavioral deficits and progressive neuropathology in progranulin-deficient mice: a mouse model of frontotemporal dementia. FASEB J. 24, 4639–4647 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10

    Filiano, A.J. et al. Dissociation of frontotemporal dementia-related deficits and neuroinflammation in progranulin haploinsufficient mice. J. Neurosci. 33, 5352–5361 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11

    Martens, L.H. et al. Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury. J. Clin. Invest. 122, 3955–3959 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12

    Akiyama, H. et al. Inflammation and Alzheimer's disease. Neurobiol. Aging 21, 383–421 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13

    McGeer, P.L. & McGeer, E.G. The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res. Brain Res. Rev. 21, 195–218 (1995).

    CAS  PubMed  Article  Google Scholar 

  14. 14

    Ilieva, H., Polymenidou, M. & Cleveland, D.W. Non–cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J. Cell Biol. 187, 761–772 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15

    Wyss-Coray, T. Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat. Med. 12, 1005–1015 (2006).

    CAS  PubMed  Google Scholar 

  16. 16

    McGeer, P.L., Rogers, J. & McGeer, E.G. Inflammation, anti-inflammatory agents and Alzheimer disease: the last 12 years. J. Alzheimers Dis. 9, 271–276 (2006).

    CAS  PubMed  Article  Google Scholar 

  17. 17

    Frank-Cannon, T.C., Alto, L.T., McAlpine, F.E. & Tansey, M.G. Does neuroinflammation fan the flame in neurodegenerative diseases? Mol. Neurodegener. 4, 47 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  18. 18

    Seshadri, S. et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. J. Am. Med. Assoc. 303, 1832–1840 (2010).

    CAS  Article  Google Scholar 

  19. 19

    Hollingworth, P. et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat. Genet. 43, 429–435 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20

    Brouwers, N. et al. Genetic variability in progranulin contributes to risk for clinically diagnosed Alzheimer disease. Neurology 71, 656–664 (2008).

    CAS  PubMed  Article  Google Scholar 

  21. 21

    Cortini, F. et al. Novel exon 1 progranulin gene variant in Alzheimer's disease. Eur. J. Neurol. 15, 1111–1117 (2008).

    CAS  PubMed  Article  Google Scholar 

  22. 22

    Viswanathan, J. et al. An association study between granulin gene polymorphisms and Alzheimer's disease in Finnish population. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 150B, 747–750 (2009).

    CAS  PubMed  Article  Google Scholar 

  23. 23

    Kelley, B.J. et al. Alzheimer disease–like phenotype associated with the c.154delA mutation in progranulin. Arch. Neurol. 67, 171–177 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  24. 24

    Perry, D.C. et al. Progranulin mutations as risk factors for Alzheimer disease. JAMA Neurol. 70, 774–778 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  25. 25

    Pereson, S. et al. Progranulin expression correlates with dense-core amyloid plaque burden in Alzheimer disease mouse models. J. Pathol. 219, 173–181 (2009).

    CAS  PubMed  Article  Google Scholar 

  26. 26

    Gliebus, G., Rosso, A. & Lippa, C.F. Progranulin and β-amyloid distribution: a case report of the brain from preclinical PS-1 mutation carrier. Am. J. Alzheimers Dis. Other Demen. 24, 456–460 (2009).

    PubMed  Article  Google Scholar 

  27. 27

    Mucke, L. et al. High-level neuronal expression of aβ 1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J. Neurosci. 20, 4050–4058 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28

    Oakley, H. et al. Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J. Neurosci. 26, 10129–10140 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29

    Chin, J. et al. Fyn kinase induces synaptic and cognitive impairments in a transgenic mouse model of Alzheimer's disease. J. Neurosci. 25, 9694–9703 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30

    Palop, J.J. et al. Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer's disease–related cognitive deficits. Proc. Natl. Acad. Sci. USA 100, 9572–9577 (2003).

    CAS  PubMed  Article  Google Scholar 

  31. 31

    Clausen, B.E., Burkhardt, C., Reith, W., Renkawitz, R. & Forster, I. Conditional gene targeting in macrophages and granulocytes using LysMcre mice. Transgenic Res. 8, 265–277 (1999).

    CAS  PubMed  Article  Google Scholar 

  32. 32

    Hickman, S.E., Allison, E.K. & El Khoury, J. Microglial dysfunction and defective β-amyloid clearance pathways in aging Alzheimer's disease mice. J. Neurosci. 28, 8354–8360 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33

    Pickford, F. et al. Progranulin is a chemoattractant for microglia and stimulates their endocytic activity. Am. J. Pathol. 178, 284–295 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34

    Chen, J. et al. SIRT1 protects against microglia-dependent amyloid-β toxicity through inhibiting NF-κB signaling. J. Biol. Chem. 280, 40364–40374 (2005).

    CAS  PubMed  Article  Google Scholar 

  35. 35

    Yin, F. et al. Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice. J. Exp. Med. 207, 117–128 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36

    Walsh, D.M. et al. Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535–539 (2002).

    CAS  Article  Google Scholar 

  37. 37

    Eimer, W.A. & Vassar, R. Neuron loss in the 5XFAD mouse model of Alzheimer's disease correlates with intraneuronal Aβ42 accumulation and caspase-3 activation. Mol. Neurodegener. 8, 2 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38

    Jawhar, S., Trawicka, A., Jenneckens, C., Bayer, T.A. & Wirths, O. Motor deficits, neuron loss, and reduced anxiety coinciding with axonal degeneration and intraneuronal Aβ aggregation in the 5XFAD mouse model of Alzheimer's disease. Neurobiol. Aging 33, 196 e29–40 (2012).

    PubMed  Article  CAS  Google Scholar 

  39. 39

    Suh, H.S., Choi, N., Tarassishin, L. & Lee, S.C. Regulation of progranulin expression in human microglia and proteolysis of progranulin by matrix metalloproteinase-12 (MMP-12). PLoS ONE 7, e35115 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40

    Cenik, B., Sephton, C.F., Kutluk Cenik, B., Herz, J. & Yu, G. Progranulin: a proteolytically processed protein at the crossroads of inflammation and neurodegeneration. J. Biol. Chem. 287, 32298–32306 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41

    Smith, K.R. et al. Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage. Am. J. Hum. Genet. 90, 1102–1107 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42

    Ahmed, Z. et al. Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging. Am. J. Pathol. 177, 311–324 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43

    Filiano, A.J. et al. Dissociation of frontotemporal dementia-related deficits and neuroinflammation in progranulin haploinsufficient mice. J. Neurosci. 33, 5352–5361 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44

    Ottis, P. et al. Human and rat brain lipofuscin proteome. Proteomics 12, 2445–2454 (2012).

    CAS  PubMed  Article  Google Scholar 

  45. 45

    Brunk, U.T. & Terman, A. Lipofuscin: mechanisms of age-related accumulation and influence on cell function. Free Radic. Biol. Med. 33, 611–619 (2002).

    CAS  PubMed  Article  Google Scholar 

  46. 46

    Laird, A.S. et al. Progranulin is neurotrophic in vivo and protects against a mutant TDP-43 induced axonopathy. PLoS ONE 5, e13368 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  47. 47

    Ryan, C.L. et al. Progranulin is expressed within motor neurons and promotes neuronal cell survival. BMC Neurosci. 10, 130 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  48. 48

    Xu, J. et al. Extracellular progranulin protects cortical neurons from toxic insults by activating survival signaling. Neurobiol Aging 32, 2326 e5–16 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  49. 49

    Kao, A.W. et al. A neurodegenerative disease mutation that accelerates the clearance of apoptotic cells. Proc. Natl. Acad. Sci. USA 108, 4441–4446 (2011).

    CAS  PubMed  Article  Google Scholar 

  50. 50

    Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51

    Butovsky, O. et al. Identification of a unique TGF-β–dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131–143 (2014).

    CAS  PubMed  Article  Google Scholar 

  52. 52

    Hickman, S.E. et al. The microglial sensome revealed by direct RNA sequencing. Nat. Neurosci. 16, 1896–1905 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53

    Pan, X.D. et al. Microglial phagocytosis induced by fibrillar β-amyloid is attenuated by oligomeric β-amyloid: implications for Alzheimer's disease. Mol. Neurodegener. 6, 45 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54

    Koenigsknecht, J. & Landreth, G. Microglial phagocytosis of fibrillar β-amyloid through a β1 integrin–dependent mechanism. J. Neurosci. 24, 9838–9846 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55

    Mueller-Steiner, S. et al. Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer's disease. Neuron 51, 703–714 (2006).

    CAS  PubMed  Article  Google Scholar 

  56. 56

    Sun, B. et al. Cystatin C–cathepsin B axis regulates amyloid β levels and associated neuronal deficits in an animal model of Alzheimer's disease. Neuron 60, 247–257 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57

    Johnson-Wood, K. et al. Amyloid precursor protein processing and Aβ42 deposition in a transgenic mouse model of Alzheimer disease. Proc. Natl. Acad. Sci. USA 94, 1550–1555 (1997).

    CAS  PubMed  Article  Google Scholar 

  58. 58

    Koo, E.H. & Squazzo, S.L. Evidence that production and release of amyloid β–protein involves the endocytic pathway. J. Biol. Chem. 269, 17386–17389 (1994).

    CAS  PubMed  Google Scholar 

  59. 59

    Krabbe, G. et al. Functional impairment of microglia coincides with β-amyloid deposition in mice with Alzheimer-like pathology. PLoS ONE 8, e60921 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60

    Sun, B. & Gan, L. Manipulation of gene expression in the central nervous system with lentiviral vectors. Methods Mol. Biol. 670, 155–168 (2011).

    CAS  PubMed  Article  Google Scholar 

  61. 61

    Hughes, R.N. The value of spontaneous alternation behavior (SAB) as a test of retention in pharmacological investigations of memory. Neurosci. Biobehav. Rev. 28, 497–505 (2004).

    CAS  PubMed  Article  Google Scholar 

  62. 62

    Laird, N.M. & Ware, J.H. Random-effects models for longitudinal data. Biometrics 38, 963–974 (1982).

    CAS  Article  PubMed  Google Scholar 

  63. 63

    Altman, D.G. & Bland, J.M. How to obtain the P value from a confidence interval. BMJ 343, d2304 (2011).

    PubMed  Article  Google Scholar 

Download references

Acknowledgements

We thank M. Finucane for statistical analyses, J. Lau and W. Weiss for technical advice, B. Miller and L. Mitic for discussions, G. Howard and A. Lucido for editorial review, J. Carroll and T. Roberts for graphics assistance, V. Shen and R. Chen for technical assistance, E.H. Koo (University of California San Diego) and P. Davies (Albert Einstein College of Medicine) for CT-15 and PHF-1 antibodies, respectively, and L. Goss for administrative assistance. This work was supported in part by the Consortium for Frontotemporal Dementia Research (L.G. and R.V.F.), the US National Institutes of Health (1R01AG036884 and R01AG030207 to L.G.) and the Stephen D. Bechtel Jr. Foundation. S.S.M. is supported by US National Institutes of Health fellowship F32NS076239, and L.H.M. is supported by US National Institutes of Health fellowship F31AG034793. Behavioral data were obtained with the help of the Gladstone Institutes' Neurobehavioral Core (supported by US National Institutes of Health grant P30NS065780).

Author information

Affiliations

Authors

Contributions

L.G., S.S.M. and S.-W.M. conceived the project and designed the experiments. S.S.M., S.-W.M., G.K., Y.Z., C.W., Y.L. and R.A. conducted experiments. L.H.M., L.P.E., M.E.W., L.M. and R.V.F. developed experimental tools or mouse models. S.S.M. and L.G. wrote the manuscript.

Corresponding author

Correspondence to Li Gan.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10 and Supplementary Tables 1–2. (PDF 73446 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Minami, S., Min, SW., Krabbe, G. et al. Progranulin protects against amyloid β deposition and toxicity in Alzheimer's disease mouse models. Nat Med 20, 1157–1164 (2014). https://doi.org/10.1038/nm.3672

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing